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Glucosidase Alpha Neutral C Promotes Influenza Virus Replication by Inhibiting Proteosome-Dependent Degradation of Hemagglutinin

ABSTRACT: The H7N9 influenza virus poses a significant threat to human health, and the mechanism by which it infects humans remains incompletely understood. Our investigation has unveiled significant insights into the role of glucosidase alpha, neutral C (ganc) gene in human H7N9 infections. Through whole genome sequencing (WGS), we identified five low-frequency functional and heterozygous variants of ganc strongly associated with human H7N9 infections compared to healthy controls. Furthermore, we observed a reduction in mRNA and protein expression of GANC following H7N9 virus infection in vitro and in vivo. Subsequent experiments involving GANC demonstrated promotion of H7N9 virus replication in a stable strain with GANC overexpression. Conversely, GANC knockdown exhibited the ability to restrict influenza A virus (IAV) replication, including H7N9, H9N2 and H1N1, both in vitro and in vivo. This inhibition was mediated by GANC's ability to promote the degradation of H7N9 hemagglutinin (HA). Moreover, we discovered that GANC knockdown facilitated the degradation of HA in a proteasome-dependent manner. The inhibition caused by GANC knockdown was mediated by promoting direct binding of HA with the proteasome 26S subunit, non-ATPase, 1 (PSMD1) and PSMD2. All the five variants in the ganc gene reduced its ability to promote H7N9 virus replication, and also diminished the levels of GANC-induced HA protein expression. Our findings revealed a novel mechanism by which GANC inhibited the proteasome-dependent degradation of HA to promote H7N9 virus replication. These results suggest that GANC may play an important role in IAV replication.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291573 | GEO | 2025/03/24

REPOSITORIES: GEO

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Glucosidase Alpha Neutral C Promotes Influenza Virus Replication by Inhibiting Proteosome-Dependent Degradation of Hemagglutinin

Project description:The H7N9 influenza virus poses a significant threat to human health, and the mechanism by which it infects humans remains incompletely understood. Our investigation has unveiled significant insights into the role of glucosidase alpha, neutral C (ganc) gene in human H7N9 infections. Through whole genome sequencing (WGS), we identified five low-frequency functional and heterozygous variants of ganc strongly associated with human H7N9 infections compared to healthy controls. Furthermore, we observed a reduction in mRNA and protein expression of GANC following H7N9 virus infection in vitro and in vivo. Subsequent experiments involving GANC demonstrated promotion of H7N9 virus replication in a stable strain with GANC overexpression. Conversely, GANC knockdown exhibited the ability to restrict influenza A virus (IAV) replication, including H7N9, H9N2 and H1N1, both in vitro and in vivo. This inhibition was mediated by GANC's ability to promote the degradation of H7N9 hemagglutinin (HA). Moreover, we discovered that GANC knockdown facilitated the degradation of HA in a proteasome-dependent manner. The inhibition caused by GANC knockdown was mediated by promoting direct binding of HA with the proteasome 26S subunit, non-ATPase, 1 (PSMD1) and PSMD2. All the five variants in the ganc gene reduced its ability to promote H7N9 virus replication, and also diminished the levels of GANC-induced HA protein expression. Our findings revealed a novel mechanism by which GANC inhibited the proteasome-dependent degradation of HA to promote H7N9 virus replication. These results suggest that GANC may play an important role in IAV replication.

2025-03-10 | PXD061732 |

Transcriptomic characterization of the novel avian-origin influenza A (H7N9) virus: specific and intermediate host-response between avian (H5N1 and H7N7) and human (H3N2) viruses.

2014-01-16 | GSE49840 | GEO

Transcriptomic characterization of the novel avian-origin influenza A (H7N9) virus: specific and intermediate host-response between avian (H5N1 and H7N7) and human (H3N2) viruses.

Project description:A novel avian-origin H7N9 influenza A virus (IAV) emerged in China in early 2013 causing mild to lethal human respiratory infections. H7N9 originated from multiple reassortment events between avian viruses and carries genetic markers of human adaptation. Determining whether H7N9 induces a host-response closer to human or avian IAV is important to better characterize this emerging virus. Here we compared the human lung epithelial cell response to infection with A/Anhui/01/13 (H7N9) or highly pathogenic avian-origin H5N1, H7N7, or human seasonal H3N2 IAV. Here, polarized confluent monolayers of Calu-3 cells were infected apically with the avian-origin IAVs A/Anhui/01/2013 (H7N9) [Anhui01], A/Netherland/219/2003 (H7N7) [NL219], A/Vietnam/1203/2004 (H5N1) [VN1203], or a human seasonal virus A/Panama/2007/1999 (H3N2) [Pan99] at an MOI of 1. Time-matched mocks were also included using the same cell stock as the rest of the samples. Culture medium (same as what the virus stock is in) was used for the mock infections. Quadruplicate wells were infected for each virus/timepoint. Measured timepoints were 3, 7, 12 and 24 hours post-inoculation and the RNA was used for transcriptional analysis via microarray.

2014-01-16 | E-GEOD-49840 | biostudies-arrayexpress

Viral determinants in H5N1 influenza A virus enable productive infection of HeLa cells

Project description:Influenza A virus (IAV) is a human respiratory pathogen that causes yearly global epidemics, and sporadic pandemics due to human adaptation of pathogenic strains. Efficient replication of IAV in different species is, in part, dictated by its ability to exploit the genetic environment of the host cell. To investigate IAV tropism in human cells, we evaluated the replication of IAV strains in a diverse subset of epithelial cell lines. HeLa cells were refractory to growth of human H1N1 and H3N2, and low pathogenic avian influenza (LPAIs) viruses. Interestingly, a human isolate of the highly pathogenic avian influenza (HPAI) virus H5N1 successfully propagated in HeLa cells to levels comparable to a human lung cell line. Heterokaryon cells generated by fusion of HeLa and permissive cells supported H1N1 growth, suggesting the absence of a host factor(s) required for replication of H1N1, but not H5N1, in HeLa cells. The absence of this factor(s) was mapped to reduced nuclear import, replication, and translation, and deficient viral budding. Using reassortant H1N1:H5N1 viruses, we found that the combined introduction of nucleoprotein (NP) and hemagglutinin (HA) from H5N1 was necessary and sufficient to enable H1N1 growth. Overall, this study suggests the absence of one or more cellular factors in HeLa cells that results in abortive replication of H1N1, H3N2, and LPAI viruses, but can be circumvented upon introduction of H5N1 NP and HA. Further understanding of the molecular basis of this restriction will provide important insights into virus-host interactions that underlie IAV pathogenesis and tropism.

2019-11-21 | GSE140759 | GEO

Segment-specific kinetics of mRNA, cRNA and vRNA during influenza infection

Project description:Influenza A virus (IAV) is a segmented negative-sense RNA virus and is the cause of major global epidemics and pandemics. The replication of IAV is complex, involving both transcription and replication, during which three distinct RNA species, namely mRNA, cRNA, and vRNA are generated for all eight genome segments. While understanding IAV replication kinetics is important for drug development and improving vaccine production, current methods for studying IAV kinetics has been limited by the ability to detect all three different RNA species in a scalable manner. Here were report the development of a novel pipeline using total stranded RNA-Seq, named Influenza Virus Enumerator of RNA Transcripts (InVERT) which allows for the simultaneous quantification of all three RNA species of IAV. Using InVERT provides a full landscape of the IAV replication kinetics, in which we found that different groups of viral genes followed different traits of kinetics. During a cycle of infection, the RNA-dependent RNA Polymerase (RdRP) produced more vRNA than mRNA while some other genes (NP, NS, HA) consistently make more mRNA than vRNA. vRNA expression levels do not correlate with the cRNA expression, suggesting complex regulations of vRNA synthesis. Furthermore, by studying the kinetics of a virus lacking the capacity to generate new polymerase complexes, we found evidence that further supports the model that cRNA synthesis requires newly synthesized RdRP and that incoming RdRP can only generate mRNA.

2021-02-19 | GSE162281 | GEO

Influenza viral RNA pulldown MS in THP-1 cells

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2021-03-25 | PXD020723 | Pride

Expression profiles of long noncoding RNAs and mRNAs in A549 cells infected by Influenza virus

Project description:Long noncoding RNAs (lncRNAs) participate in regulating many biological processes. However, their roles in influenza A virus (IAV) pathogenicity are largely unknown. Here, we analyzed the expression profile of lncRNAs and mRNAs in the H3N2-infected cells and H7N9-infected cells by high-throughput sequencing

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Influenza-induced inflammation drives pneumococcal otitis media

Project description:Influenza A virus (IAV) predisposes individuals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes. Here, we demonstrate that the viral hemagglutinin (HA) mediates bacterial OM by inducing a pro-inflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings show that it is the inflammatory response that mediates pneumococcal replication; not viral suppression of the immune system or epithelial damage. This study provide the first evidence that HA induced inflammation drives pneumococcal replication in the middle ear cavity, which has important consequences to the treatment of pneumococcal OM.

2013-01-01 | GSE41098 | GEO

An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA

Project description:The emergence of new highly pathogenic and drug-resistant influenza strains urges the development of novel therapeutics for influenza A virus (IAV). Here, we report the discovery of an anti-IAV microbial metabolite called APL-16-5 that was originally isolated from the plant endophytic fungus Aspergillus sp. CPCC 400735. APL-16-5 binds to both the E3 ligase TRIM25 and IAV polymerase subunit PA, leading to TRIM25 ubiquitination of PA and subsequent degradation of PA in the proteasome. This mode of action conforms to that of a proteolysis targeting chimera which employs the cellular ubiquitin-proteasome machinery to chemically induce the degradation of target proteins. Importantly, APL-16-5 potently inhibits IAV and protects mice from lethal IAV infection. Therefore, we have identified a natural microbial metabolite with potent in vivo anti-IAV activity and the potential of becoming a new IAV therapeutic. The antiviral mechanism of APL-16-5 opens the possibility of improving its anti-IAV potency and specificity by adjusting its affinity for TRIM25 and viral PA protein through medicinal chemistry.

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